JAC Surveillance of the overall consumption of antibacterial drugs in humans, domestic animals and farmed fish in Norway in 1992 and 1996

Transcription

1 Journal of Antimicrobial Chemotherapy (1999) 43, JAC Surveillance of the overall consumption of antibacterial drugs in humans, domestic animals and farmed fish in Norway in 1992 and 1996 Kari Grave a, Egil Lingaas b, Marit Bangen c and Marit Rønning d a Department of Veterinary Pharmacy and c Veterinary Drug Information Centre, The National Hospital Pharmacy, Pilestredet 32, N-0027/Department of Pharmacology, Microbiology and Food Hygiene, Norwegian College of Veterinary Medicine, PO Box 8146 Dep., N-0033 Oslo; b The National Hospital, Department of Hospital Infection Control, Pilestredet 32, N-0027 Oslo; d Norwegian Medicinal Depot AS, PO Box 100 Veitvet, 0518 Oslo, Norway The annual overall consumption of antibacterial drugs in Norway, categorized into human use, use in domestic animals and in farmed fish, was estimated from wholesaler and feed-mill sales statistics. Comprehensive data on drug consumption in human medicine in Norway are published on a regular basis on behalf of the drug authorities. These data, including use of antibacterial drugs, are expressed as the number of defined daily doses (DDD)/1000 inhabitants/ year. DDD cannot be employed to compare antibiotic consumption in human and veterinary medicine as it is possible to calculate such data for only a few veterinary drugs. The only parameter for which data are generally available, so far, is the amount used in kilograms of active substance, which is the unit of measurement chosen in this study. It was found that annual overall sales of antibacterial drugs in Norway, including antibacterial and ionophore feed additives, decreased from 77 tonnes in 1992 to 49 tonnes in 1996, a 37% reduction. The use in 1996 in human medicine, animals and farmed fish was 35 tonnes, 13 tonnes and 1 tonne, respectively. While the annual amounts used in human medicine remained unchanged from 1992 to 1996, therapeutic use in fish farming declined by 96%. In domestic animals, therapeutic use and use as feed additives declined by 17% and 5%, respectively. During the study period, the size of the human and domestic animal populations at risk remained almost constant, while the biomass (weight) of farmed fish at risk increased by >100%. This implies that both the absolute and relative consumption of antibacterial drugs in Norway decreased substantially during the study period. The use of antibacterial drugs, both in humans and in domestic animals, has changed in favour of penicillins, this being in accordance with general recommendations. The reduction in the use of antibacterial drugs in farmed fish has been almost solely due to the introduction of oil-adjuvanted vaccines against furuncolosis. It is concluded that the decline in the amount of antibacterial drugs used in domestic animals, and the changes with regard to choice of drugs, could be mainly attributed to changes in prescribing behaviour following advice and recommendations. Moreover, the overall use of antibacterial drugs in Norway is very low compared with that in most other countries and has been significantly reduced during the 1990s. Introduction The association between increased rates of antibacterial drug use and antibacterial drug resistance has been documented for nosocomial infections and communityacquired infections 1,2 as well as following veterinary use for therapy and growth promotion. Selective pressure exerted by widespread antibacterial drug use is the driving force in the development of antibacterial drug resistance. Moreover, resistance factors in human and animal pathogens and commensals, particularly those carried on mobile genes, can spread rapidly within human and animal populations and from animals to humans. 3,4 As resistance develops in rough relation to the extent of use, its emergence and *Tel: ; Fax: The British Society for Antimicrobial Chemotherapy 243

2 K. Grave et al. spread should be prevented primarily by limiting the use of antibiotics. Comprehensive data on drug consumption in human medicine in Norway are published on a regular basis on behalf of the drug authorities. 5 These data, including use of antibacterial drugs, are expressed as the number of defined daily doses (DDD)/1000 inhabitants/year. For antibacterial drugs, these data provide a basis for the evaluation of therapeutic trends in bacterial infections and of human exposure to antibacterial drugs. In veterinary medicine, it is only possible to calculate such data for a small range of veterinary antibacterial drugs and animal species. 6 Hence, the use of DDD to compare human and veterinary prescribing patterns is not possible. Data on antibacterial drug consumption in humans in Norway in terms of kilograms of active substance are not yet available. Comparable data on antibacterial drug use in human medicine, domestic animals and farmed fish are therefore lacking. Both quantitative and qualitative records of antibacterial drug use are essential, not only to enable evaluation of the impact of antibiotic policy, but also to allow the determination of possible correlations between the use of certain groups of antibacterial drugs and the emergence of resistance (resistance-epidemiology). The main aims of this study were to develop a comparative method to quantify the overall use of antibacterial drugs in humans, domestic animals and farmed fish in Norway, and to analyse trends in the prescribing patterns of these drugs based on consumption in 1992 and Materials and methods In Norway, antibacterial drugs for therapeutic use in humans, domestic animals and farmed fish are prescription drugs only. Moreover, both human and veterinary antibacterial drugs have to be dispensed through pharmacies which are supplied solely by drug wholesalers. Hospitals have to be supplied either by pharmacies or wholesalers. An exemption from the pharmacy/wholesaler monopoly has been granted for medicated feed (i.e. feeds into which drugs for therapeutic use are mixed before sale). Medicated feeds have to be prescribed by veterinary surgeons, and are produced and delivered by feed mills authorized by the Directorate of Health. In Norway, medicated feeds produced and supplied by feed mills are used only in farmed fish, not in livestock (Thorvik, T., personal communication). The reason for this practice is the small size of livestock herds in Norway, compared with most other European countries. However, herd/flock treatment of other livestock with antibacterial drugs is possible, again subject to veterinary prescription, with drugs being administered either through drinking water or in medicated feed prepared on the farm. 7 In Norway, the sales figures of drugs from wholesalers and feed mills roughly equals the use of drugs (see Discussion). In this study, antibacterial drug use is therefore used as a synonym for sales figures of antibacterial drugs. Overall sales data, representing sales from the Norwegian drug wholesalers to pharmacies and hospitals and from feed mills to fish farms, are recorded by the Norwegian Medicinal Depot AS, a state-owned drug wholesaler, on behalf of the Directorate of Health. Such data were obtained from the Norwegian Medicinal Depot AS for the purpose of this study. In Norway, the Anatomical Therapeutic Chemical (ATC) classification system is used to classify human medicinal products and the ATC veterinary (ATCvet) classification is used for veterinary medicinal products. 8,9 These systems were used in this study. All approved human and veterinary antibacterial specialities belonging to the following ATC/ATCvet (Q) groups were included in the study: gastrointestinal infections (A07AA/QA07AA), uterine infections (G04AA AB AC/QG01AA AE), and antibacterial drugs for systemic use (J01 J04/QJ), including intramammary dose applicators (QJ51). In Norway, a selection of medicated feeds for farmed fish are approved by the drug authorities for therapeutic use only and are classified as pharmaceutical specialities. These products are included in the QJ group. Additionally, this study included a raw material product containing 20% oxytetracycline (oral powder) which is used in pigs, and an ex tempore product containing 50% phenoxymethylpenicillin (po powder) which is used in poultry. Both these products are prescribed for therapeutic use only. Additionally, human and veterinary antibacterial drugs sold on exemption from marketing authorization and stocked on a regular basis by the wholesalers were also included. The data for these preparations were calculated only for Dermatological, eye and ear preparations were not included in this study. The amount of active substance, in kilograms, was chosen as the unit of measurement. The amounts, in kilograms of active substance, of human and veterinary antibacterial agents supplied by wholesalers to pharmacies and hospitals, and by feed mills, were calculated from sales figures. The data for benzyl penicillin salts and esters (procaine penicillin and penethamate hydriodide) were converted to the corresponding values for benzyl penicillin. 10,11 In order to estimate the potential of selection pressure due to oral use of antibacterial drugs in humans and animals, the data were split according to the route of administration. Data on the size of the human and livestock populations, and of the total biomass (tonnes) of farmed fish at risk in 1992 and 1996, were obtained from the Norwegian Statistical Yearbooks and while data on pigs and poultry were obtained from R. Bruholt (personal communication). For farmed fish, the data are expressed as amounts, in tonnes, sold. In Norway, a limited number of antibacterial feed additives are licensed for growth-promoting purposes in 244

3 Consumption of antibacterial drugs in Norway poultry, and sales figures of these substances are included in this study. Anticoccidial drugs (coccidiostats) authorized as feed additives and which also possess antibacterial activity (ionophore antibiotics) are also included in the study, even though these substances are not classified as antibacterials within the European Union (Council Directive 70/524/EEC). Sales data for these products are presented in this paper to give a picture of the overall selective pressure exerted by antibacterial drug use in Norway. Ionophore antibacterial drugs are not used in human medicine. Annual sales figures for feed additives, in kilograms of active substances according to target animal, were obtained from the Norwegian Agricultural Inspection Service. 14 Results During the study period, there was a total reduction of 37% in the overall use of antibacterial drugs in Norway (Table I). Therapeutic use in domestic animals and farmed fish declined by 76% from 1992 to While overall use in domestic animals and farmed fish, both as therapeutics and as feed additives with antibacterial effects, declined by 67% from 1992 to 1996, use in human medicine was almost constant, a slight increase of 0.6% being recorded. The sales, in 1996, of human and veterinary antibacterial drugs not licensed on the Norwegian market contributed only 67 kg and 32 kg active substances, respectively. These figures are not included in following presentation. Sales of antibacterial veterinary drugs for therapeutic use in domestic animals declined by 17% from 1992 to 1996 (Table I). The overall use in domestic animals of antibacterial drugs for therapeutic use and as feed additives fell by 13%, while the amount of antibacterial drugs sold for treatment of bacterial infections in farmed fish fell by 96%. The use of antibiotic feed additives declined by 95%, while the use of ionophore coccidiostats increased by 22% (Table II). The use of penicillins for the treatment of domestic animals increased from 31% of the total therapeutic use in Table I. Sales (in kilograms of active substance) in Norway of approved antibacterial drugs for therapeutic use and feed additives (antibacterial growth-promoters and coccidiostats with antibacterial effects) Antibiotic use Human medicine 34,496 34,694 Veterinary medicine domestic animals fish farming 27, Feed additives Total 76,955 48, to 38% in 1996, while the corresponding use of aminoglycosides (dihydrostreptomycin) constituted 31% in 1992 and 24% in 1996 (Table III). -Lactamase-sensitive penicillins were the predominant penicillins used in domestic animals in both 1992 (98%) and 1996 (96%). The contribution of tetracyclines to drug use in domestic animals fell from 7.7% in 1992 to 4.3% in In human medicine, consumption of penicillins represented 54% and 57% of the total annual use of antibacterial drugs in 1992 and 1996, respectively. -Lactamase-sensitive penicillins were the most extensively prescribed penicillin group in human medicine in both 1992 (86%) and 1996 (84%). Human medicine contributed 45% to the total amount of antibacterial drugs used in Norway in 1992; the corresponding figure for 1996 was higher, 71% (Figure 1). Overall use in Norway of quinolones and tetracyclines declined by 92% and 68%, respectively, from 1992 to The contributions to the total use of quinolones and tetracyclines of preparations approved for use in human and veterinary medicine (domestic animals and farmed fish) respectively, in 1992 and 1996, are presented in Figure 2. Total human and livestock populations, and biomass (tonnes) of farmed fish in 1992 and 1996 in Norway, at risk of possibly being treated with antibacterial drugs, are presented in Table IV. As regards route of administration, the proportion of antibacterial therapeutics administered as injectable drugs in domestic animals was 53% and 52% in 1992 and 1996 respectively, while oral administration accounted for 33% in both years, when measured as kilograms of active substance (Table V). Oral administration through the feed is the sole route used for systemic antibacterial drug treatment in farmed fish. Of the overall consumption of antibacterial drugs in domestic animals, both as therapeutics and as feed additives, oral formulations comprised 56% in 1992 and 58% in 1996 (kilograms of active substance). Table II. Sales (in kilograms of active substance) in Norway of feed additives with antibacterial effects (antibiotics and ionophore coccidiostats) according to target animal (Norwegian Agricultural Inspection Service, 1997) Feed additives Target animal Antibiotics avoparcin chicken/turkey zinc bacitracin hens/turkey total Coccidiostats lasalocid chicken/turkey monensin chicken/turkey salinomycin chicken narasin chicken total

4 K. Grave et al. Table III. Sales (in kilograms of active substance) in Norway, in 1992 and 1996, of antibacterial drugs for therapeutic use in human medicine (H), domestic animals (A) and farmed fish (F) according to class of drug (ATC/ATCvet classification). Data were obtained from Norwegian wholesalers Class of drugs H A F H A F Aminoglycosides Amphenicols Carbapenems Cephalosporins and related agents Glycopeptides Hydrazide derivatives Imidazoles Lincosamides Macrolides Methenamine products Monobactams Nitrofurans Penicillins -lactamase sensitive 15, , lactamase resistant extended spectrum Pleuromutilins Polyene antibiotics Polymyxins 0, Quinolones , Rifamycins Steroid antibacterials Sulphonamides Tetracyclines Trimethoprim and derivatives Total 34, ,485 34, In human medicine, consumption of peroral antibacterial drugs constituted 92% and 91%, of total sales in 1992 and 1996, respectively. The corresponding figures for injectable antibacterial drugs were 7% and 8%. Of the injectable drugs, the -lactamase-sensitive penicillins made the major contribution, both in humans (Table VI) and in domestic animals (Table V). The number of antibacterial substances approved for human and veterinary use on the Norwegian market increased from 1992 to 1996 by 11% and 22%, respectively (Table VII). Only one new substance (florfenicol) was approved for use in farmed fish over the same period. Discussion The sales figures of antibacterial drugs for therapeutic use presented in this study are based on annual statistics on drugs sold by Norwegian wholesalers to pharmacies and hospitals. Because pharmacies only stock drugs on a short term basis (Haug, K., unpublished data), the wholesalers figures roughly correspond to the actual amounts of the drugs prescribed during the study period. The feed mills report sales of antibacterial drugs for therapeutic use in farmed fish to the Norwegian Medicinal Depot AS. These figures reflect the actual prescribing patterns because the feed mills dispense medicated feed directly to the fish farmers only on veterinary prescription. Antibacterial feed additives are sold directly to the farmers, so the data give a rough picture of the use of these substances. Drugs which are for use in humans and which are also prescribed and sold for use in animals cannot be differentiated and are therefore recorded as sold for human use and included as such in the overall sales data. Methenamine products for human use and ionophore coccidiostats constitute two important groups of antibacterial agents not usually included in studies on overall use of antibacterial drugs. They were, however, included in the 246

5 Consumption of antibacterial drugs in Norway Table IV. Total human and livestock (main species) populations, and biomass (tonnes) of farmed fish in 1992 and 1996 in Norway, at risk of possibly being treated with antibacterial drugs (Norwegian Statistical Yearbook, 1993; 1997; Statistics Norway, unpublished data a ) Population Figure 1. Distribution of total sales in 1992 and 1996 of antibacterial drugs approved for use in humans ( ), in domestic animals ( ), in farmed fish ( ) and as feed additives ( ). Figure 2. Contributions to total sales in 1992 and 1996 of quinolones and tetracyclines approved for use in human ( ) and in veterinary medicine (domestic animals and farmed fish ( )). present study as they may exert a selective pressure on the bacterial flora. In conclusion, the sales figures presented in this study are considered to represent the overall use of antibacterial drugs in Norway in 1992 and There are several limitations to the use of weight as a comparator for antibiotic consumption and its impact on the development of resistance. Several other factors are also important, such as antibacterial potency, spectrum of activity, mode of action and the number of macro- and microorganisms involved. Moreover, factors such as the Human 4,273,634 4,369,957 Cattle 981,300 1,005,800 Sheep ( 1 year old) 1,083,100 1,032,300 Dairy goats 61,700 57,900 Breeding pigs a 93,100 92,500 Slaughter pigs a 1,214,700 1,328,500 Hens a 3,714,200 3,460,600 Slaughter chickens (broilers) a 16,850,642 23,264,300 Atlantic salmon 124, ,426 Rainbow trout ,267 number of species exposed to the drug and the fate of the drug in the body of the target species and in the environment are also important. Sales figures, expressed in kilograms of active substance, should therefore be interpreted with care and at least each substance group should be assessed for trends. The rationale of this approach would be to get closer to a relevant measure of selective pressure on antibacterial resistance. To avoid some of the drawbacks of using the kilogram as the unit of measurement, the concept of DDD has been developed for application in studies in human medicine; 8 population number or hospital days is used as the denominator when comparing drug use. DDD can also be used indirectly to estimate the number of individuals treated, this figure being derived by dividing DDD by the average duration of treatment, if known. DDD can be applied to compare human antibiotic consumption between institutions and between countries, though as yet only a few countries publish statistics on DDD. In the Nordic countries, DDD statistics in human medicine have been published since the beginning of The overall human consumption of antibacterial drugs in Norway amounted to 15.1 DDD/1000 inhabitants/year in 1992 and decreased to 14.5 DDD in Finland, Iceland and Sweden have a higher human consumption of antibacterial drugs than Norway. 15 Because the figures published from Denmark do not include use in hospitals, as do the figures from the other Nordic countries, the Danish figures are not comparable with consumption in other Nordic countries. 15 DDD cannot be employed to compare antibiotic consumption in human and veterinary medicine as it is possible to calculate such data for only a few veterinary drugs. The only parameter for which data are generally available, so far, is the amount used, in kilograms of active substance. The present study revealed that in Norway, overall sales of 247

6 K. Grave et al. Table V. Sales (in kilograms of active substance) in Norway in 1992 and 1996 of antibacterial drugs for therapeutic use in domestic animals (excluding farmed fish). Data were obtained from Norwegian wholesalers Class of drugs iu inj imam po iu inj imam po Aminoglycosides Amphenicols Imidazoles Lincosamides Macrolides Penicillins -lactamase sensitive lactamase resistant extended spectrum Pleuromutilins Quinolones Sulphonamides Tetracyclines Trimethoprim and derivatives Total Abbreviations: iu, intrauterine; inj, injectable; imam, intramammary; po, oral. antibacterial drugs, including feed additives with antibacterial effects for use in domestic animals, decreased by 37% during the period , from 76,955 kg to 48,792 kg. This reduction was entirely due to a fall in the consumption of veterinary medicines, particularly those used in fish farming, whereas amounts used in humans remained unchanged. The decline in the use of antibacterial drugs in domestic animals, especially in farmed fish, has been due to several factors, the most important of which are discussed below. Because of the increasing attention being focused on antibacterial drug resistance, Norwegian livestock farming organizations initiated a campaign aiming to reduce the use of antibacterial drugs (in kilograms of active substance) by 25% over a 5 year period ( ), 1995 being chosen as the reference year. As drugs used to treat bovine mastitis make up a substantial proportion of the antibacterial drugs used in veterinary medicine, comprehensive guidelines on drug therapy in mastitis were published to support this campaign. 16 These guidelines are intended to serve as a basis for rational drug therapy in bovine mastitis, the aim being to reduce the use of antibacterial drugs in this connection. Several conferences and meetings were arranged to follow up both the campaign and the guidelines, focusing on the desirability of increasing the relative use of penicillin, with a corresponding reduction in the prescribing of benzyl penicillin and dihydrostreptomycin combinations and of tetracyclines. During the period , the therapeutic use of antibacterial drugs in traditional veterinary medicine declined by 17%, the main part of this reduction occurring in 1996, when use was reduced by 14% compared with It is important to note that the size of the livestock population at risk remained almost constant, the increase which took place from 1995 to 1996 being very slight. The reported annual frequencies of bacterial diseases in food animals were the same in 1996 as in The reduction in the use of antibacterial drugs in domestic animals can therefore be attributed almost solely to changes in veterinary prescribing patterns, due to more prudent drug use and the application of better diagnostic criteria. An important contribution to the general decline in the use of antibacterial drugs in domestic animals comes from the reduced frequency with which antibacterial drug therapy is employed in cases of chronic mastitis in cattle (Mørk, T., personal communication). Another important change in veterinary prescribing behaviour found in the present study was the relative increase in the prescribing of penicillins, with a corresponding decrease in the amount of aminoglycosides and tetracyclines prescribed for use in domestic animals. The fall in consumption of aminoglycosides was due to less frequent prescribing of combined preparations of benzyl penicillin and dihydrostreptomycin. 17 It is concluded that the campaign initiated by the Norwegian livestock farming organizations seems to have been very successful so far. Of the sulphonamides sold for use in domestic animals, sulphamethoxypyridazine contributed 1409 kg and 1088 kg in 1992 and 1996, respectively (Grave, G., unpublished data). 17 The main indication for this drug is the treatment 248

7 Consumption of antibacterial drugs in Norway Table VI. Sales (in kilograms of active substance) in Norway in 1992 and 1996 of antibacterial drugs for therapeutic use in humans. Data were obtained from Norwegian wholesalers Class of drug ivag inj po ivag inj po Aminoglycosides a Amphenicols Carbapenems Cephalosporins and related agents Glycopeptides Hydrazide derivatives Imidazoles Lincosamides Macrolides Methenamine products Monobactams Nitrofurans Penicillins -lactamase sensitive , ,639 -lactamase resistant extended spectrum Polyene antibiotics Polymyxins Quinolones Rifamycins Steroid antibacterials Sulphonamides Tetracyclines Trimethoprim Total , ,706 Abbreviations: ivag, intravaginal; inj, injectable; po, oral. a Additionally, 0.09 kg of gentamicin formulated for implantation in connection with surgery, was sold in each year. Table VII. The number of active substances and antibacterial pharmaceutical preparations approved for the Norwegian market in 1992 and 1996 Preparations for humans Preparations for domestic animals No. of substances No. of preparations of mastitis of sheep. Based on estimated frequencies of mastitis in sheep and the recommended treatment dose, it can be estimated that most of the sulphamethoxypyridazine sold is indeed used for treatment of mastitis in sheep. Pharmacokinetic studies and studies on the inhibitory effects of sulphamethoxypyridazine, however, indicate that the clinical efficacy of this form of therapy of mastitis in sheep is uncertain. 18,19 The implication is that there is potential for further reduction in the use of antibacterial drugs in domestic animals in Norway. The rapid expansion of the Norwegian fish farming industry was accompanied by recurrent problems with bacterial infectious diseases. This in turn led to the periodic use of large amounts of antibacterial drugs in the 1980s and the beginning of the 1990s. 6 In 1989, furunculosis became endemic in several parts of Norway for the first time and 249

8 K. Grave et al. caused severe losses. However, from 1992 to 1994, the use of antibacterial drugs in farmed fish decreased from 27,485 kg to 6144 kg active substance and since 1994, annual consumption has remained fairly constant, at around 1 tonne. 6 During this period, sales of farmed fish increased by 100%. It has been shown that the introduction of oiladjuvanted vaccines against furuncolosis in 1992 was the single most important factor contributing to the substantial reduction in the use of antibacterial drugs in fish farming in Norway since The overall reduction in Norway in the use of quinolones (92%) and of tetracyclines (68%) in the study period has almost solely been due to the use of oil-adjuvanted vaccines in furunculosis. The use of the antibacterial feed additives avoparcin and zinc bacitracin declined by 95% from 1992 to An important reason for this was that avoparcin was prohibited in Norway for use as a growth promoter from 31 May 1995, because an association between the use of avoparcin and the prevalence of vancomycin-resistant entrococci was reported Moreover, the Norwegian pig and poultry industry has voluntarily agreed not to use antibacterial feed additives, apart from ionophores; as a consequence the use of zinc bacitracin is now slight. When avoparcin was withdrawn from the market in Norway, narasin was authorized as a feed additive as an alternative agent to prevent necrotic enteritis in chicken. In consequence of the withdrawal of avoparcin, the use of ionophore feed additives increased substantially (22%) during the study period. The overall use of feed additives (in kilograms of active substance) with antibacterial effect nevertheless declined by 5%. This also contributed to the overall reduction of 67% in the use of antibacterial drugs in domestic animals and farmed fish which took place in Norway from 1992 to The few studies so far published on overall antibacterial drug use in veterinary medicine in other countries are mainly from Sweden In only one of these studies 26 was the methodology used to study the consumption of antibacterial drugs for therapeutic purposes in domestic animals the same as in the present study. The Swedish study 26 showed that sales of antibacterial drugs used for therapeutic purposes in domestic animals in Sweden fell from 23,207 kg active substance in 1992 to 18,521 kg in 1996, a reduction of 20%, which was similar to the 17% reduction in Norway during the same period. The Swedish data on the consumption of feed additives with antibacterial effect are not fully comparable with the data from the present study. However, as in Norway, the use of ionophores in Sweden has increased slightly in the 1990s, while the number of animals at risk in both countries has remained almost constant from 1992 to It can therefore be concluded that the overall use, in kilograms of active substances, of antibacterial drugs in domestic animals has declined from 1992 to 1996 both in Norway and Sweden. In Denmark, the consumption of antimicrobial drugs in animals has been estimated as part of the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme. 27 The therapeutic use of antibacterial drugs in Denmark in 1995 was estimated to be 49.6 tonnes of active substance, while the total sales of antibacterial feed additives amounted to 93.9 tonnes of active substance. 27 The estimated use, of antibacterial drugs for therapeutic purposes, in the Netherlands in 1990 was 300 tonnes of active substance, and as feed additives 300 tonnes. 28 The corresponding figures for the USA in 1985 were 1100 tonnes and 7000 tonnes, respectively. 29 Publications or reports from Denmark, the Netherlands, USA and other countries presenting data on consumption of antibacterial drugs in humans or animals do not give the data source, inclusion criteria, or the classification system used. Nor are data about number of animals at risk of being treated with an antibacterial drug presented in these studies It is therefore difficult to compare the data with those from the present study. All antibacterial drugs for veterinary therapeutic use in Norway are on prescription only, have to be dispensed through pharmacies, and are classified according to the ATCvet classification system. This makes it easy to collect valid and comparable data on the consumption of veterinary antibacterial agents, and thus to survey overall use and trends in prescribing patterns. This distribution system for veterinary drugs is identical to those existing in other Nordic countries. The fact that veterinary drugs for therapeutic use are distributed through pharmacies, both to animal owners and for direct use by veterinarians, implies that there are no economic incentives to prescribe antibacterial drugs. This is different from the situation in most European countries. 30 Moreover, in Norway promotional activities by the drug companies directed at the veterinarians is thought to be negligible compared with the situation in countries where pharmaceutical companies are allowed to sell drugs directly to veterinarians. Drug prices are set by the Norwegian drug authorities and the drug companies are not allowed to offer discounts directly to veterinarians in order to influence the prescribing patterns. Although comparable studies are lacking, there is reason to believe that both the absolute and relative use of antibacterial therapeuticals in domestic animals in Norway are low compared with those in most other European countries. Nevertheless, there is probably still a significant potential for reducing antibacterial drug use in human medicine, and also for a further reduction in veterinary use in Norway. The modest use of antibacterial drugs in human and veterinary medicine in Norway may be explained by the strict policy which has been implemented concerning the approval of new drugs. Until 1 January 1994, Norwegian drug legislation included the so-called need clause, which allowed the approval of new drugs only if they could be shown to have significant advantages over drugs already registered in Norway. In this context, the potential for the development of drug resistance was one of the criteria taken into account. 250

9 Consumption of antibacterial drugs in Norway As a consequence of the European Economic Area agreement (between the EU and EFTA countries), Norway had to revoke the need clause from 1 January The present study showed that there was an increase in the number of new substances and preparations approved for use both in human and veterinary medicine in Norway during the study period. Nevertheless, the use of antibacterial drugs in animals decreased over the same period, while use in humans remained constant from 1992 to As far as we know, little data has been published comparing the use of antibacterial drugs in humans and animals on a national basis. In the USA, it has been estimated that about half, by weight, of the antibiotics sold are used in livestock farming with almost 90% of agricultural use being for prophylaxis or growth promotion rather than for treatment of diseased animals. 29 In both human and veterinary medicine, criteria for antibiotic use should include the use of such drugs only when they are clinically indicated, and the selection of the appropriate agent, dose and duration of therapy. In addition, antibacterial drugs used in veterinary medicine should not exert selection pressure with regard to the development by bacteria of antibiotic resistance to drugs used in humans. With these principles in mind, reservations could be raised against current veterinary prescribing patterns for three classes of antibiotics in Norway: aminoglycosides, quinolones and sulphonamides. Veterinary use (amount) in Norway in 1996 accounted for 99%, 69% and 57%, respectively, of total consumption of these classes of drugs. The sales in 1996 of tetracyclines in human medicine represented 85% of the overall therapeutic use of this group of drugs in Norway, while 87% of the total amounts of penicillins was for human use. Although published data on antibacterial drug use are available for only a few other countries, there is reason to believe that the situation with regard both to the amounts used and the therapeutic profile of antibacterial drug use in human medicine in Norway compares favourably with that in most other industrialized countries. This study showed that, in Norway, narrow spectrum -lactamase-sensitive penicillins accounted for 48%, and the penicillin group as a whole for 57% of total human consumption. Consumption of cephalosporins (5.1% of overall human use) is fairly modest, but increased by 23% from 1992 to The use of quinolones in human medicine is also modest, representing 1.2% of total human use in Of the tetracyclines, only oxytetracycline is used in domestic animals and farmed fish in Norway. The proportion of the sales in human medicine of each tetracycline substance remained almost constant during the study period. It is thus concluded that there has really been a reduction in the use of tetracyclines in Norway. The extent of selection of resistant bacterial strains depends of a number of factors, including type of antibacterial drug, the way it is used (route of administration, dose and duration) and the number of bacteria exposed to the antibacterial drug in question. 26 The present study has shown that, in Norway, oral use of antibacterial drugs (including feed additives and ionophores) represented 58% of the total consumption in livestock in 1996, the corresponding figure being 92% in human medicine. As the intestine contains a large number of various bacterial species, it is suggested 26 that oral administration of antibacterial drugs may result in the development of a higher proportion of resistant bacterial strains than parenteral administration and that the intestine then may act as reservoir for resistant bacteria. In the risk assessment of antibacterial drug resistance, splitting the data into oral and injectable use may thus be important. However, this hypothesis needs further investigation, including studies on the impact of different routes of administration on antibacterial drug resistance and therapeutic outcome. It is important that comparable data on the consumption of antibacterial drugs in humans, animals and farmed fish in different countries be obtained in the future, not only to evaluate the impact of antibiotic policies, but also to estimate the selective pressure and to look for possible correlations between the use of specific groups of antibiotics and the emergence of resistance. If antibacterial drug consumption data are to be reliable and comparable, they will have to be gathered according to strict methodological standards, of which the most essential continue to be the use of a common drug classification system and of an internationally agreed unit of measurement. 8,31 Acknowledgement This work was supported in part by a grant from the Research Council of Norway. References 1. McGowen, J. E. (1983). Antimicrobial resistance in hospital organisms and its relation to antibiotic use. Reviews of Infectious Diseases 5, Baquero, F., Martínez-Beltran, J. & Loza, E. (1991). A review of antibiotic resistance patterns of Streptococcus pneumoniae in Europe. Journal of Antimicrobial Chemotherapy 28, Suppl. C, Kruse, H. (1994). Antimicrobial resistance epidemiological aspects. PhD thesis. Norwegian College of Veterinary Medicine, Oslo. 4. American Society for Microbiology. (1995). Report of the ASM task force on antibiotic resistance. Antimicrobial Agents and Chemotherapy, Suppl., Øydvin, K. (1997). Drug Consumption in Norway Norwegian Medicinal Depot AS, Oslo, Norway. 6. Grave, K., Markestad, A. & Bangen, M. (1996). Comparison in prescribing patterns of antibacterial drugs in salmonid farming in Norway during the periods and Journal of Veterinary Pharmacology and Therapeutics 19, Tørisen, H. M. (1996). The Norwegian Compendium of Veterinary Medicines, 14th edn. Felleskatalogen AS, Oslo, Norway. 251

10 K. Grave et al. 8. WHO Collaborating Centre for Drug Statistics Methodology. (1996). Guidelines for ATC Classification and DDD Assignment. Oslo, Norway. 9. Nordic Council on Medicines. (1997). ATCvet Index NLN Publication No. 43. Uppsala, Sweden. 10. Reynolds, J. E. F. (1996). In Martindale. The Extra Pharmacopoeia, 31st edn, p Royal Pharmaceutical Society, London. 11. Budavari, S., O Neil, M. J., Smith, A., Heckelman, P. E. & Kinneary, J. F. (1996). In The Merck Index, 12th edn, p Merck & Co., USA. 12. Longva, S. (1993). Norwegian Statistical Yearbook, 112th edn, pp. 33, 195. Statistics Norway, Oslo/Kongsvinger. 13. Longva, S. (1997). Norwegian Statistical Yearbook, 116th edn, pp. 54, 295. Statistics Norway, Oslo/Kongsvinger. 14. Glende, H. B. & Helø, E. (1998). Feed Additives Statistics. Circular 3/98, p. 4. Norwegian Agricultural Inspection Service, Ås, Norway. 15. Nordic Council on Medicines. (1996). Nordic Statistics on Medicines NLN Publication No. 43. Uppsala, Sweden. 16. Tørud, E., Lang-Ree, R., Raage, A., Støverud, S., Sivertsen, T., Ødegaard, S. A. et al. (1996). Strategier for å redusere forbruk av antibakterielle midler i storfeproduksjonen med særlig vekt på behandling av mastitt. The Norwegian Cattle Health Program. Ås, Norway. 17. Grave, K. & Rønning, M. (1997). Forskrivningsmønsteret for antibakterielle midler registrert til veterinærmedisinsk bruk i Norge i Norsk Veterinærtidsskrift 109, Indrebø, A. & Ødegaard, S. A. (1986). Sulfametoksypyridazin (Longamid) og sulfonamid til søye. Norsk Veterinærtidsskrift 98, Jarp, J., Falk, K. & Ødegaard, S. A. (1988). Behandling med sulfonamid ved mastitt. Norsk Veterinærtidsskrift 100, Markestad, M. & Grave, K. (1997). Reduction of antibacterial drug use in Norwegian fish farming due to vaccination. Developments in Biological Standardization 90, Aarestrup, F. M. (1995). Occurrence of glycopeptide resistance among Enterococcus faecium isolates from conventional and ecological poultry farms. Microbial Drug Resistance 1, Klare, I., Heier, H., Claus, H., Böhme, G., Marin, S., Seltmann, G. et al. (1995). Enterococcus faecium strains with vana-mediated high-level glycopeptide resistance isolated from animal foodstuffs and fecal samples of humans in the community. Microbial Drug Resistance 1, van den Bogaard, A., London, N., Driessen, C. & Stobberingh, E. (1996). Prevalence of resistant faecal bacteria in turkeys, turkey farmers and turkey slaughterers. In Program and Abstracts of the Thirty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans. Abstract E27, p. 86. American Society for Microbiology, Washington, DC. 24. Wierup, M., Wold-Troell, M. & Franklin, A. (1989). Antibiotikaförbrukningen hos djur i Sverige under perioden Svensk Veterinärtidning 41, Björnerot, L., Franklin, A. & Tysén, E. (1996). Usage of antibacterial and antiparasitic drugs in animals in Sweden between 1988 and Veterinary Record 139, 282 6; Erratum: Veterinary Record 139, Swedish Ministry of Agriculture. (1997). Antimicrobial Feed Additives. Report from the Commission on Antimicrobial Feed Additives, SOU 132. Nordstedts Tryckeri AB, Stockholm. 27. Bager, F. (1997). In Consumption of Antimicrobial Agents and Occurrence of Antimicrobial Resistance in Bacteria from Food Animals, Food and Humans in Denmark, No. 1, pp Danish Zoonosis Centre, Copenhagen. 28. van den Bogaard, A. E. (1997). Antimicrobial resistance relation to human and animal exposure to antibiotics. Journal of Antimicrobial Chemotherapy 40, US Congress, Office of Technology Assessment. (1995). In Impacts of Antibiotic-Resistant Bacteria, OTA-H-629, pp Government Printing Office, Washington, DC. 30. Kidd, A. R. M. (1992). Distribution of veterinary medicines within the European community. EEC reference CNS/91B8-5300/MI/ Dukes, M. N. G. (1993). Drug Utilization Studies. Methods and Uses. WHO Regional Publications, European Series, No. 45. WHO Regional Office for Europe, Copenhagen. Received 23 February 1998; returned 27 April 1998; revised 19 May 1998; accepted 7 September